PATH-42. Histo-molecular and survival study of high-grade astrocytoma with piloid features

High-grade astrocytoma with piloid features (HGAP) is a rare glial tumor defined by an astrocytic morphology and a distinct DNA methylation profile. The clinical behavior, histological grading, and response to treatment for these tumors are not well established. We analyzed 59 HGAPs by DNA methylation and Heidelberg classifier 12.5 at NYU Langone Health. Copy number variations (CNV) were analyzed using Conumee package. Clinical, pathological, molecular, and survival data were retrieved from medical records. Overall survival was analyzed by Survival pack in R. The median age at diagnosis was 38.5 years. The most common location was the posterior fossa, followed by cerebral hemispheres. DNA methylation showed that all cases clustered with the methylation class “HGAP.” The copy number profile was complex in 51 cases, and simple in 8. 52/59 cases demonstrated homozygous loss of CDKN2A/B. Recurrent amplifications were noted in MDM2(10), CDK4(8), PPM1D(5), PDGFRA(5), and TERT(3) genes. DNA and RNA NGS was available for 24 patients and showed recurrent alterations of ATRX(12), NF1(6), FGFR1(6), PIK3CA(3), BRAF(2), TSC2(2), H3K27M(1), ERBB2(1). The median overall survival rate was 22 months. Prolonged progression free survival was recorded in only one patient (12 years). Their tumor was characterized by a favorable histology and simple copy number profile. Repeat analysis by DNA methylation was available for three cases: an HGAP that progressed to GBM_CBM after 3 years, a pilocytic astrocytoma that progressed to HGAP, then to pedHGG_RTK1, and a stable HGAP on 2 resections 4 months apart. We show that HGAPs are high-grade, molecularly complex tumors that frequently occur in nonresectable sites. They may represent a successor for pilocytic astrocytoma, and a precursor for glioblastoma, especially in NF1 patients. Although rare cases with favorable histology and simple copy number profiles may show a prolonged progression free survival, the median overall survival is comparable to other high-grade gliomas.